PRMT1-mediated arginine methylation redirects a metastasis-promoting transcriptional output of SMAD4 in pancreatic cancer

Although SMAD4 is frequently altered in PDAC, the majority of tumors retain wild-type SMAD4, which paradoxically acquires pro-metastatic functions during disease progression. How SMAD4 transcriptional output is reprogrammed to support metastasis in advanced PDAC remains poorly understood.Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical modifier that promotes a metastasis-promoting transcriptional state of SMAD4.

PRMT1 catalyzes asymmetric dimethylation of SMAD4 at arginine 272 (R272), a modification that does not alter SMAD4 expression but stabilizes nuclear SMAD2/3-SMAD4 complexes and redirects SMAD4 chromatin engagement toward epithelial-mesenchymal transition (EMT) gene programs. Mechanistically, R272-methylated SMAD4 promotes the recruitment of a BRG1-CTCF transcriptional complex, enabling chromatin-dependent activation of pro-metastatic transcriptional outputs.Importantly, pharmacological inhibition of PRMT1, particularly in combination with BRG1 degradation, dismantles methylation-dependent SMAD4 transcriptional complexes, suppresses EMT programs, and markedly reduces liver metastasis in preclinical PDAC models.Together, these findings uncover a post-translational mechanism that governs SMAD4 transcriptional specificity and identify PRMT1-dependent methylation as a therapeutic vulnerability in SMAD4-wild-type pancreatic cancer.